In macaques, progesterone stimulates epithelial cell proliferation in the endometrial basalis and inhibits estrogen-dependent epithelial proliferation in the endometrial functionalis. We have shown that antiprogestins inhibit estrogen-dependent growth of the primate endometrium. Here we report the effects of long-term treatment of intact cycling rhesus macaques with low doses of the potent antiprogestin ZK 137 316 (ZK ) on endometrial epithelial cell proliferation. Four groups of monkeys were injected daily for 5 cycles with 3 doses of ZK (none [vehicle], 0.01, 0.03 and 0.1 mg /kg body weight, i.m.). Uteri (n=3/ group) were collected on day 22 of the 5th cycle in the vehicle, 0.01 and 0.03 mg/kg groups, or 6-7 days after the estradiol peak in the 0.1 mg/kg group. Results of immuno-staining for Ki-67 antigen (% positive cells) and histological analysis of mitotic index (number of mitotic cells per 1000 epithelial cells) is shown in Table 1. Luteal phase P in vehicle treated controls inhibited cell proliferation in the endometrial functionalis (both Ki-67 staining and mitotic index) and stimulated proliferation in the basalis. ZK-treated animals showed a dose-dependent increase in the abundance of Ki-67-positive epithelial cells in the functionalis, and a dose dependent decrease in Ki-67 positive cells in basalis epithelium. This suggests that ZK inhibited P induced basalis proliferation, and by blocking P suppression of estrogen action, allowed estrogen to stimulate epithelial proliferation in the functionalis. However, at higher doses ZK appeared to also reduce the number of mitotic cells in the functionalis even though Ki-67 staining (an estrogen effect) was elevated. This suggests that ZK can block estrogen-stimulated cells in the functionalis from completing the cell cycle. These data further suggest that blockade of the cell cycle may contribute to inhibitory effects that antiprogestins have on endometrial development.